Characterization of behavioral changes in T-maze alternation from dopamine D₁ agonists with different receptor...

Dopamine D₁ receptor agonists have been shown to improve working memory, but often have a non-monotonic (inverted-U) dose-response curve. One hypothesis is that this may reflect dose-dependent differential engagement of D₁ signaling pathways, a mechanism termed functional selectivity or signaling bias.

To test this hypothesis, we compared two D₁ ligands with different signaling biases in a rodent T-maze alternation task. Both tested ligands (2-methyldihydrexidine and CY208243) have high intrinsic activity at cAMP signaling, but the former also has markedly higher intrinsic activity at D₁-mediated recruitment of β-arrestin. The spatial working memory was assessed via the alternation behavior in the T-maze where the alternate choice rate quantified the quality of the memory and the duration prior to making a choice represented the decision latency.

Both D₁ drugs changed the alternate rate and the choice latency in a dose-dependent manner, albeit with important differences. 2-Methyldihydrexidine was somewhat less potent but caused a more homogeneous improvement than CY208243 in spatial working memory. The maximum changes in the alternate rate and the choice latency tended to occur at different doses for both drugs.

These data suggest that D₁ signaling bias in these two pathways (cAMP vs β-arrestin) has complex effects on cognitive processes as assessed by T-maze alternation. Understanding these mechanisms should allow the identification or discovery of D₁ agonists that can provide superior cognitive enhancement.